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The origin of primates has long been associated with an increased emphasis on manual grasping and touch. Precision touch, facilitated by specialized mechanoreceptors in glabrous skin, provides critical sensory feedback for grasping-related tasks and perception of ecologically-relevant stimuli. Despite its importance, studies of mechanoreceptors in primate hands are limited, in part due to challenges of sample availability and histological methods. Dermatoglyphs have been proposed as alternative proxies of mechanoreceptor density. We investigated the relationships between mechanoreceptors (Meissner and Pacinian corpuscles), dermatoglyphs, and demography in the apical finger pads of 15 juvenile to adult rhesus macaques (Macaca mulatta) from a free-ranging population at Cayo Santiago Primate Field Station (Puerto Rico). Our results indicate substantial interindividual variation in mechanoreceptor density (Meissner corpuscles: 11.9-43.3 corpuscles/mm2; Pacinian corpuscles: 0-4.5 corpuscles/mm2). While sex and digit were generally not associated with variation, there was strong evidence of a developmental effect. Specifically, apical pad length, Meissner corpuscle size, and Pacinian corpuscle depth increased while mechanoreceptor densities decreased throughout juvenescence, suggesting that primate mechanoreceptors change as fingers grow during adolescence and then stabilize at physical maturity. We also found Meissner corpuscle density was significantly associated with dermatoglyph ridge width and spacing, such that density predicted by a dermatoglyph model was strongly correlated with observed values. Dermatoglyphs thus offer a useful proxy of relative Meissner corpuscle density in primates, which opens exciting avenues of noninvasive research. Finally, our results underscore the importance of considering demographic factors and methodology in comparative studies of primate touch.
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Radiation injury, either from radiotherapy or a mass-casualty event requires a health care system that can efficiently allocate resources to patients. We conducted a comprehensive transcriptome analysis of whole blood from a nonhuman primate model that received upper thoracic radiation (9.8-10.7 Gy). Blood samples were collected at multiple time points, extending up to 270 days post-irradiation with a minimum n = 6 for initial time points (Day 3-Day 40) and a total number of n = 28 primates. No males receiving the higher dose survived to Day 270. Using the Elastic Net model in R we found that pooling biomarkers from Day 3-21 increased our accuracy in discerning survival time, pleural effusion or dose compared to using biomarkers specific to a single day. For survival data, in predicting short term (less than 90 day), medium term (Day 91-269) or long-term survival (Day 270), prediction accuracy using only Day 3 data was 0.14 (95% Confidence Interval (CI) 0.1, 0.19) while pooled data for Male and Female was 0.76 (CI 0.69, 0.82). When pooled data was divided by biological sex, accuracy was 0.7 (CI 0.58, 0.8) for pooled data from Males and 0.84 (CI 0.76, 0.91) for Females. The development of RNA biomarkers as a tool to aid in clinical decision-making could significantly improve patient care in cases of radiation injury, whether from radiotherapy or mass-casualty events. Further validation and clinical translation of these findings could lead to improved patient care and management strategies in cases of radiation exposure.
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Biomarcadores , Animales , Masculino , Biomarcadores/sangre , Femenino , ARN/sangre , ARN/genética , Macaca mulatta , Tórax/efectos de la radiación , Perfilación de la Expresión Génica , TranscriptomaRESUMEN
The etiology of Parkinson's disease (PD) remains elusive, and the limited availability of suitable animal models hampers research on pathogenesis and drug development. We report the development of a cynomolgus monkey model of PD that combines adeno-associated virus (AAV)-mediated overexpression of α-synuclein into the substantia nigra with an injection of poly(ADP-ribose) (PAR) into the striatum. Our results show that pathological processes were accelerated, including dopaminergic neuron degeneration, Lewy body aggregation, and hallmarks of inflammation in microglia and astrocytes. Behavioral phenotypes, dopamine transporter imaging, and transcriptomic profiling further demonstrate consistencies between the model and patients with PD. This model can help to determine the mechanisms underlying PD impacted by α-synuclein and PAR and aid in the accelerated development of therapeutic strategies for PD.
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Dependovirus , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas , Macaca fascicularis , Enfermedad de Parkinson , Poli Adenosina Difosfato Ribosa , alfa-Sinucleína , Animales , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Dependovirus/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/genética , Poli Adenosina Difosfato Ribosa/metabolismo , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Humanos , Sustancia Negra/metabolismo , Sustancia Negra/patología , Masculino , Microglía/metabolismo , Microglía/patología , Astrocitos/metabolismo , Astrocitos/patologíaRESUMEN
Designer receptors exclusively activated by designer drugs (DREADDs) are engineered G-protein-coupled receptors that afford reversible manipulation of neuronal activity in vivo. Here, we introduce size-reduced DREADD derivatives miniDq and miniDi, which inherit the basic receptor properties from the Gq-coupled excitatory receptor hM3Dq and the Gi-coupled inhibitory receptor hM4Di, respectively, while being approximately 30% smaller in size. Taking advantage of the compact size of the receptors, we generated an adeno-associated virus (AAV) vector carrying both miniDq and the other DREADD family receptor (κ-opioid receptor-based inhibitory DREADD [KORD]) within the maximum AAV capacity (4.7 kb), allowing us to modulate neuronal activity and animal behavior in both excitatory and inhibitory directions using a single viral vector. We confirmed that expressing miniDq, but not miniDi, allowed activation of striatum activity in the cynomolgus monkey (Macaca fascicularis). The compact DREADDs may thus widen the opportunity for multiplexed interrogation and/or intervention in neuronal regulation in mice and non-human primates.
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Dependovirus , Drogas de Diseño , Vectores Genéticos , Macaca fascicularis , Neuronas , Animales , Dependovirus/genética , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Drogas de Diseño/farmacología , Drogas de Diseño/química , Humanos , Conducta Animal/efectos de los fármacos , Ratones , Receptores Opioides kappa/metabolismo , Receptores Opioides kappa/genética , Masculino , Células HEK293 , Clozapina/análogos & derivados , Clozapina/farmacologíaRESUMEN
This Optimized Multiparameter Immunofluorescence Panel (OMIP) reports on the development of a mass cytometry panel for broad immunophenotyping of leukocytes from bronchoalveolar lavage from rhesus macaques. Using this panel, we were able to identify myeloid populations such as macrophages, neutrophils, monocytes, myeloid and plasmacytoid DCs, basophils and lymphoid cell lineages including B cells, natural killer (NK) cells, mucosal associated invariant T (MAIT) cells, γδ T cells, CD4 T cells, CD8 ß T cells, CD8 T cells, and innate lymphoid cells (ILCs). We also included markers for defining memory, differentiation (CCR7, CD28, CD45RA), homing potential (CXCR3), cytotoxic potential (perforin, granzyme B, granzyme K), cell activation/differentiation (HLA-DR, CD69, IgD) and effector function (CD154, IFN-γ, TNF, IL-2, IL-17A, IL-6, IL-1ß, CCL4 and CD107a). This panel was optimized on cryopreserved, bronchoalveolar lavage and splenocytes collected from rhesus macaques. The antibodies selected in this panel are human-specific antibodies that have been shown to cross-react with non-human primates except for CD45 clone D058-1283 which is specific for non-human primates.
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During development, precursor cells are continuously and intimately interacting with their extracellular environment, which guides their ability to generate functional tissues and organs. Much is known about the development of the neocortex in mammals. This information has largely been derived from histological analyses, heterochronic cell transplants, and genetic manipulations in mice, and to a lesser extent from transcriptomic and histological analyses in humans. However, these approaches have not led to a characterization of the extracellular composition of the developing neocortex in any species. Here, using a combination of single-cell transcriptomic analyses from published datasets, and our proteomics and immunohistofluorescence analyses, we provide a more comprehensive and unbiased picture of the early developing fetal neocortex in humans and non-human primates. Our findings provide a starting point for further hypothesis-driven studies on structural and signaling components in the developing cortex that had previously not been identified.
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Metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced stage, metabolic dysfunction-associated steatohepatitis (MASH), are increasingly recognized as a global health issue. This study examines the role of small RNAs in the spleen of MASH using a non-human primate model. We performed high-throughput small RNA sequencing on spleen tissues from MASH-primates, revealing significant alterations in the expression of small non-coding RNAs, especially miRNAs. Notably, miR-96, miR-182, miR-183, and miR-122 showed differential expression in MASH spleens. Predictive and validation studies have identified potential target genes, such as PTX3 and NFIX, that were significantly dysregulated in spleens of MASH. These findings characterized small RNAs in spleen of MASH and offer a novel insight for further research for MASH.
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The physiological and pathological changes in the human body caused by environmental pressures are collectively referred to as the Exposome. Human society is facing escalating environmental pollution, leading to a rising prevalence of associated diseases, including respiratory diseases, cardiovascular diseases, neurological disorders, reproductive development disorders, among others. Vulnerable populations to the pathogenic effects of environmental pollution include those in the prenatal, infancy, and elderly stages of life. Conducting Exposome mechanistic research and proposing effective health interventions are urgent in addressing the current severe environmental pollution. In this review, we address the core issues and bottlenecks faced by current Exposome research, specifically focusing on the most toxic ultrafine nanoparticles. We summarize multiple research models being used in Exposome research. Especially, we discuss the limitations of rodent animal models in mimicking human physiopathological phenotypes, and prospect advantages and necessity of non-human primates in Exposome research based on their evolutionary relatedness, anatomical and physiological similarities to human. Finally, we declare the initiation of NHPE (Non-Human Primate Exposome) project for conducting Exposome research using non-human primates and provide insights into its feasibility and key areas of focus. SYNOPSIS: Non-human primate models hold unique advantages in human Exposome research.
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To encode allocentric space information of a viewing object, it is important to relate perceptual information in the first-person perspective to the representation of an entire scene which would be constructed before. A substantial number of studies investigated the constructed scene information (e.g., cognitive map). However, only few studies have focused on its influence on perceptual processing. Therefore, we designed a visually guided saccade task requiring monkeys to gaze at objects in different locations on different backgrounds clipped from large self-designed mosaic pictures (parental pictures). In each trial, we presented moving backgrounds prior to object presentations, indicating a frame position of the background image on a parental picture. We recorded single-unit activities from 377 neurons in the posterior inferotemporal (PIT) cortex of two macaques. Equivalent numbers of neurons showed space-related (119 of 377) and object-related (125 of 377) information. The space-related neurons coded the gaze locations and background images jointly rather than separately. These results suggest that PIT neurons represent a particular location within a particular background image. Interestingly, frame positions of background images on parental pictures modulated the space-related responses dependently on parental pictures. As the frame positions could be acquired by only preceding visual experiences, the present results may provide neuronal evidence of a mnemonic effect on current perception, which might represent allocentric object location in a scene beyond the current view.
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Neuronas , Percepción Espacial , Lóbulo Temporal , Animales , Lóbulo Temporal/fisiología , Percepción Espacial/fisiología , Masculino , Neuronas/fisiología , Movimientos Sacádicos/fisiología , Estimulación Luminosa/métodos , Percepción Visual/fisiología , Macaca , Macaca mulattaRESUMEN
The Thrifty Female Hypothesis states that females preserve more of their energy reserves during winter than males because of the sex-specific time frame of energy allocation for reproduction. As males reactivate their reproductive axis before the mating period, while females mainly allocate energy during gestation and lactation, we hypothesized that males would have to use shorter torpor bouts and longer periods of normothermic activity to promote spermatogenesis during winter, a period of low food availability. Here, we applied an acute two-week 80% caloric restriction in male and female gray mouse lemurs shortly before the mating period. We found evidence of thriftier phenotypes in wintering females, which performed deeper and longer torpor bouts than males and ultimately lost less body mass. Our results thus support the thrifty female hypothesis in a seasonally breeding primate and reinforce the concept of a sex-biased trade-off in using torpor, which might ultimately benefit reproduction and survival.
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An older wild female chimpanzee (Pan troglodytes) was found dead with a large calcium oxalate stone in the renal pelvis. Histopathological changes included glomerulosclerosis, interstitial nephritis and fibrosis, focal mineralization, and medial hypertrophy. Urinary albumin-creatinine-ratio showed increased values from 15 months before death. Causes of the kidney disease remain unconfirmed.
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Enfermedades del Simio Antropoideo , Cálculos Renales , Pan troglodytes , Insuficiencia Renal Crónica , Animales , Côte d'Ivoire , Femenino , Enfermedades del Simio Antropoideo/patología , Cálculos Renales/veterinaria , Cálculos Renales/etiología , Insuficiencia Renal Crónica/veterinaria , Insuficiencia Renal Crónica/patología , Resultado Fatal , Oxalato de Calcio/análisisRESUMEN
INTRODUCTION: This study aimed to explore the characteristics of post-stroke sleep dysfunction and verify their association with gut dysbiosis and the related amino acid metabolism disorders. This was achieved by using fecal microbiota transplantation (FMT) in a non-human primate stroke model. METHODS: Twenty adult male cynomolgus monkeys were divided into the sham (n = 4), middle cerebral artery occlusion (MCAO, n = 5), MCAO + FMT (n = 3), and donor (n = 8) groups. The MCAO+FMT group received FMT at post-MCAO week 4. Sleep parameters, gut microbiota, gamma-aminobutyric acid (GABA), and glutamine (Gln) in the cerebrospinal fluid (CSF) were measured at baseline and postoperative weeks 4, 8, and 12. RESULTS: At postoperative weeks 4, 8, and 12, the MCAO group showed decreased sleep efficiency, measured as the percentage of sleep during the whole night (82.3 ± 3.2 % vs 91.3 ± 2.5 %, 79.0 ± 3.75 % vs 90.8 ± 3.2 %, and 69.5 ± 4.8 % vs 90.5 ± 2.7 %; all P < 0.05), lower relative abundance of Lactobacillus (all P < 0.05), and reduced GABA concentrations in the CSF (317.3 ± 30.6 nmol/L vs 437.7 ± 25.6 nmol/L, 303.1 ± 48.9 nmol/L vs 4 40.9 ± 37.8 nmol/L, and 337.9 ± 49.4 nmol/L vs 457.4 ± 39.2 nmol/L; all P < 0.05) compared with the sham group. Sleep efficiency at post-FMT weeks 4 and 8 (84.7 ± 1.1 % vs 79.0 ± 3.75 %, and 84.1 ± 2.0 % vs 69.5 ± 4.8 %; both P < 0.05) and GABA concentration in the CSF at post-FMT week 4 (403.1 ± 25.4 nmol/L vs 303.1 ± 48.9 nmol/L, P < 0.05) was higher in the MCAO+FMT group than in the MCAO group. CONCLUSIONS: Post-stroke sleep dysfunction in monkeys is characterized by impaired sleep coherence, associated with decreased levels of probiotics such as Lactobacillus, GABA, and Gln in the CSF and can be ameliorated using FMT.
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Disbiosis , Microbioma Gastrointestinal , Infarto de la Arteria Cerebral Media , Macaca fascicularis , Trastornos del Sueño-Vigilia , Animales , Masculino , Microbioma Gastrointestinal/fisiología , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/líquido cefalorraquídeo , Trastornos del Sueño-Vigilia/etiología , Trastornos del Sueño-Vigilia/líquido cefalorraquídeo , Trastornos del Sueño-Vigilia/metabolismo , Trasplante de Microbiota Fecal/métodos , Ácido gamma-Aminobutírico/líquido cefalorraquídeo , Ácido gamma-Aminobutírico/metabolismo , Aminoácidos/líquido cefalorraquídeo , Aminoácidos/metabolismo , Glutamina/metabolismo , Glutamina/líquido cefalorraquídeoRESUMEN
The subthalamic nucleus (STN) plays critical roles in the motor and cognitive function of the basal ganglia (BG), but the exact nature of these roles is not fully understood, especially in the context of decision-making based on uncertain evidence. Guided by theoretical predictions of specific STN contributions, we used single-unit recording and electrical microstimulation in the STN of healthy monkeys to assess its causal, computational roles in visual-saccadic decisions based on noisy evidence. The recordings identified subpopulations of STN neurons with distinct task-related activity patterns that related to different theoretically predicted functions. Microstimulation caused changes in behavioral choices and response times that reflected multiple contributions to an 'accumulate-to-bound'-like decision process, including modulation of decision bounds and evidence accumulation, and to non-perceptual processes. These results provide new insights into the multiple ways that the STN can support higher brain function.
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Toma de Decisiones , Macaca mulatta , Núcleo Subtalámico , Animales , Núcleo Subtalámico/fisiología , Toma de Decisiones/fisiología , Neuronas/fisiología , Masculino , Estimulación Eléctrica , Movimientos Sacádicos/fisiologíaRESUMEN
How people vote often defies rational explanation. Physical traits sometimes sway voters more than policies do-but why? Here we show that rhesus macaques, who have no knowledge about political candidates or their policies, implicitly predict the outcomes of U.S. gubernatorial and senatorial elections based solely on visual features. Given a pair of candidate photos, monkeys spent more time looking at the loser than the winner, and this gaze bias predicted not only binary election outcomes but also the candidates' vote share. Analysis of facial features revealed candidates with more masculine faces were more likely to win an election, and vote share was a linear function of jaw prominence. Our findings endorse the idea that voters spontaneously respond to evolutionarily conserved visual cues to physical prowess and that voting behavior is shaped, in part, by ancestral adaptations shared with nonhuman primates.
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In humans, cognitive aging is highly variable, with some individuals experiencing decline while others remain stable, and different cognitive domains exhibiting uneven vulnerability to aging. The neural mechanisms driving this intra- and inter-individual variability are not fully understood, making longitudinal studies in translational models essential for elucidating the timelines and processes involved. The common marmoset (Callithrix jacchus), a short-lived nonhuman primate, offers an unprecedented opportunity to conduct longitudinal investigations of aging and age-related disease over a condensed time frame, in a highly translatable animal model. The potential of the marmoset as a model for cognitive aging is indisputable, but a comprehensive cognitive battery tailored for longitudinal aging studies has not yet been developed, applied, or validated. This represents a critical missing piece for evaluating the marmoset as a model and understanding the extent to which marmoset cognitive aging mirrors the patterns found in humans, including whether marmosets have individual variability in their vulnerability to age-related cognitive decline. To address this, we developed a comprehensive touchscreen-based neuropsychological test battery for marmosets (MarmoCog), targeting five cognitive domains: working memory, stimulus-reward association learning, cognitive flexibility, motor speed, and motivation. We tested a large cohort of marmosets, ranging from young adults to geriatrics, over several years. We found significant variability in cognitive aging, with the greatest decline occurring in domains dependent on the prefrontal cortex and hippocampus. Additionally, we observed significant inter-individual variability in vulnerability to age-related cognitive decline: some marmosets declined across multiple domains, others in just one, and some showed no decline at all. This pattern mirrors human cognitive aging, solidifies the marmoset as an advantageous model for age-related cognitive decline, and provides a strong foundation for identifying the neural mechanisms involved.
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Large-scale analysis of single-cell gene expression has revealed transcriptomically defined cell subclasses present throughout the primate neocortex with gene expression profiles that differ depending upon neocortical region. Here, we test whether the interareal differences in gene expression translate to regional specializations in the physiology and morphology of infragranular glutamatergic neurons by performing Patch-seq experiments in brain slices from the temporal cortex (TCx) and motor cortex (MCx) of the macaque. We confirm that transcriptomically defined extratelencephalically projecting neurons of layer 5 (L5 ET neurons) include retrogradely labeled corticospinal neurons in the MCx and find multiple physiological properties and ion channel genes that distinguish L5 ET from non-ET neurons in both areas. Additionally, while infragranular ET and non-ET neurons retain distinct neuronal properties across multiple regions, there are regional morpho-electric and gene expression specializations in the L5 ET subclass, providing mechanistic insights into the specialized functional architecture of the primate neocortex.
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Neuronas , Transcriptoma , Animales , Neuronas/metabolismo , Neuronas/citología , Transcriptoma/genética , Neocórtex/citología , Neocórtex/metabolismo , Corteza Motora/citología , Corteza Motora/metabolismo , Masculino , Lóbulo Temporal/citología , Lóbulo Temporal/metabolismo , Macaca mulattaRESUMEN
Early human trophoblast development has remained elusive due to the inaccessibility of the early conceptus. Non-human primate models recapitulate many features of human development and allow access to early postimplantation stages. Here, we tracked the pre- to postimplantation transition of the trophoblast lineage in superficially implanting marmoset embryos in vivo. We differentiated marmoset naive pluripotent stem cells into trophoblast stem cells (TSCs), which exhibited trophoblast-specific transcriptome, methylome, differentiation potential, and long-term self-renewal. Notably, human TSC culture conditions failed to support marmoset TSC derivation, instead inducing an extraembryonic mesoderm-like fate in marmoset cells. We show that combined MEK, TGF-ß/NODAL, and histone deacetylase inhibition stabilizes a periimplantation trophoblast-like identity in marmoset TSCs. By contrast, these conditions differentiated human TSCs toward extravillous trophoblasts. Our work presents a paradigm to harness the evolutionary divergence in implantation strategies to elucidate human trophoblast development and invasion.
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Callithrix , Diferenciación Celular , Transducción de Señal , Trofoblastos , Trofoblastos/metabolismo , Trofoblastos/citología , Humanos , Animales , Femenino , Células Madre/metabolismo , Células Madre/citología , Células Madre Pluripotentes/metabolismo , Células Madre Pluripotentes/citologíaRESUMEN
The increase in urinary tract infections (UTI) caused by antibiotic-resistant Escherichia coli requires the development of new therapeutic agents and prophylactic vaccines. To evaluate the efficacy of new lead candidates, we implemented a cynomolgus macaque UTI challenge model that mimics human uncomplicated cystitis in response to transurethral challenge with a multidrug-resistant (MDR) E. coli serotype O25b ST131 isolate. E. coli fimbrial adhesin FimH and O-antigens are separately under clinical evaluation by others as vaccine candidates to prevent UTI and invasive urosepsis disease, respectively. Accordingly, we assessed the protective efficacy of three 50-µg intramuscular doses of a novel recombinant FimH antigen adjuvanted with liposomal QS21/MPLA compared with saline placebo in groups of nine animals. A third group was vaccinated with this FimH formulation in combination with 1 µg each of a four-valent mixture of serotype O1a, O2, O6, and O25b O-antigen CRM197 lattice glycoconjugates. Both vaccines elicited high levels of serum FimH IgG and adhesin blocking antibodies at the time of bacterial challenge and, for the combination group, O-antigen-specific antibodies. Following bacterial challenge, both vaccinated groups showed >200- and >700-fold reduction in bacteriuria at day 2 and day 7 post-infection compared with placebo, respectively. In parallel, both vaccines significantly reduced levels of inflammatory biomarkers IL-8 and myeloperoxidase in the urine at day 2 post-infection relative to placebo. Results provide preclinical proof-of-concept for the prevention of an MDR UTI infection by these new vaccine formulations.
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Adhesinas de Escherichia coli , Modelos Animales de Enfermedad , Infecciones por Escherichia coli , Vacunas contra Escherichia coli , Escherichia coli , Proteínas Fimbrias , Macaca fascicularis , Infecciones Urinarias , Animales , Adhesinas de Escherichia coli/inmunología , Adhesinas de Escherichia coli/genética , Infecciones por Escherichia coli/prevención & control , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/microbiología , Infecciones Urinarias/prevención & control , Infecciones Urinarias/microbiología , Infecciones Urinarias/inmunología , Proteínas Fimbrias/inmunología , Proteínas Fimbrias/genética , Vacunas contra Escherichia coli/inmunología , Vacunas contra Escherichia coli/administración & dosificación , Escherichia coli/genética , Escherichia coli/inmunología , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , FemeninoRESUMEN
Immunological priming-in the context of either prior infection or vaccination-elicits protective responses against subsequent Mycobacterium tuberculosis (Mtb) infection. However, the changes that occur in the lung cellular milieu post-primary Mtb infection and their contributions to protection upon reinfection remain poorly understood. Using clinical and microbiological endpoints in a non-human primate reinfection model, we demonstrated that prior Mtb infection elicited a long-lasting protective response against subsequent Mtb exposure and was CD4+ T cell dependent. By analyzing data from primary infection, reinfection, and reinfection-CD4+ T cell-depleted granulomas, we found that the presence of CD4+ T cells during reinfection resulted in a less inflammatory lung milieu characterized by reprogrammed CD8+ T cells, reduced neutrophilia, and blunted type 1 immune signaling among myeloid cells. These results open avenues for developing vaccines and therapeutics that not only target lymphocytes but also modulate innate immune cells to limit tuberculosis (TB) disease.
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Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Granuloma , Inmunomodulación , Mycobacterium tuberculosis , Reinfección , Animales , Linfocitos T CD4-Positivos/inmunología , Mycobacterium tuberculosis/inmunología , Reinfección/inmunología , Granuloma/inmunología , Granuloma/microbiología , Linfocitos T CD8-positivos/inmunología , Tuberculosis/inmunología , Tuberculosis/microbiología , Modelos Animales de Enfermedad , Pulmón/inmunología , Pulmón/microbiología , Pulmón/patología , Humanos , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiologíaRESUMEN
A thorough characterization of induced pluripotent stem cells (iPSCs) used with in vitro models or therapeutics is essential. Even iPSCs derived from a single donor can exhibit variability within and between cell lines, which can lead to heterogeneity in results and hinder the promising future of cell replacement therapies. In this study, the cell seeding density of human and rhesus monkey iPSCs was tested to maximize the cell line-specific yield of the generated cardiomyocytes. We found that, despite using the same iPSC generation and differentiation protocols, the cell seeding density for the cell line-specific best differentiation efficiency could differ by a factor of four for the four cell lines used here. In addition, the cell lines showed differences in the range of cell seeding densities that they could tolerate without the severe loss of differentiation efficiency. Overall, our data show that the cell seeding density is a critical parameter for the differentiation inefficiency of primate iPSCs to cardiomyocytes and that iPSCs generated with the same episomal approach still exhibit considerable heterogeneity. Therefore, individual characterization of iPSC lines is required, and functional comparability with in vivo processes must be ensured to warrant the translatability of in vitro research with iPSCs.